This invention relates to a method of peripheral venous treatment of a mammals e.g., patients (human or animal) who suffers from renal disease, cancer cachexia and those receiving ventilatory support. More specifically, it relates to xylitol as the sole carbohydrate which together with amino acids in the absence of fat emulsions is used for peripheral vein administration and will unexpectedly preserve body protein in above mentioned patients.
A hypocaloric preparation provides 400 to 1200k cal per day which delivers less than the patient's total needs and is usually accomplished with peripheral glucose which sometimes includes amino acids. Hypercaloric preparations provide 1500 up to 10,000k cal per day. The present invention is unexpectedly superior to current hypocaloric regimens of carbohydrates with or without amino acids.
In renal failure and cancer cachexia insulin resistance and elevated catabolic hormones result in a net release of amino acids, primarily from muscle and connective tissue, but also from kidney and gastrointestinal mucosa. The increased extracellular amino acid pool is associated with an enhanced gluconeogenesis in the liver to meet the requirements of those tissues that can use only glucose. In addition, there is an increased synthesis of fibrinogen and acute phase globulins in the liver (Blackburn, G. L., Phinney, S. D., in Surgical Physiology, ed. Burke, J. F., Philadelphia, C. V. Mosby and Co., 1980) as well as an accelerated protein synthesis rate in the cellular immune system (Gross, R. L., Newberne, P. M. Physiol. Rev., 60, 188, 1980). Mobilization of fatty acids aids in fulfulling the energy requirements of the liver. Despite augmented fatty acid oxidation, fewer ketone bodies are formed to serve as an alternative energy source for heart, skeletal muscle, brain, and kidney.
Even hypocaloric glucose infusions reduce fatty acid oxidation and ketone body production. The failure of ketone body production in the liver contributes to a severe energy deficit in muscle tissue, which may lead to an accelerated proteolysis. Since skeletal muscle constitutes about 40 percent of body mas, the metabolism of muscle tissue plays a major role in the mobilization and oxidation of amino acids in the periphery. Branched chain amino acids and intermediates of some dispensible amino acids are oxidized in skeletal muscle to fulfill the energy deficit and to provide nitrogen groups and carbon skeletons for the synthesis of alanine and glutamine. These two amino acids are then released at rates greater than their concentration in muscle tissue, and the increased availability to gluconeogenic substrates, mainly alanine, advanes glucose production in the liver. Glucose given even in small quantities (150-300 g/day) as a component of parenteral nutrition therapies can be deleterious to the liver in such a situation, because it cannot reduce gluconeogenesis (Long, C. L., Jeevanandam, M., Kim, B. M., Kinney, J. M., Am. J. Clin. Nutr., 30, 1340, 1977) but rather stimulate lipogenesis. The use of hypertonic carbohydrate mixtures which are exclusively for central venous administration are frequently used in clinical practice and consist of glucose, fructose, and xylitol in a preparation of 1:1:1 at a total dosage of 600 g/day (Georgieff, M., Geiger, K., Bratsch, H. et al. in Recent Advances in Clinical Nutrition I, ed. Howard, A., Baird, J., Mc.L., John Libbey and Company, Ltd, 1981). Glucose in these solutions is reported to stimulate hepatic lipogenesis. It has been observed that using xylitol for hypercaloric use in hypertonic preparations is no better than using only glucose.
In liver tissue, glucose-6-P is metabolized by 4 main metabolic pathways. ##STR1##
After an oral glucose meal, only 20-30% of the glucose taken up by liver is directly oxidized while the rest is converted to glycogen or triglycerides and then secreted as very low density lipoprotein-triglycerides (VLDL-TG). During continuous high carbohydrate intakes such as in currently available total parenteral nutrition regimens, the amount of glucose being metabolized in the glycolytic pathway and converted to VLDL-TG is increased, due to an activation of the enzymes involved in that process. The amount of glucose metabolized in the pentose phosphate shunt varies from 10 to over 30% of total liver glucose uptake. In this cycle ribose and deoxyribose are synthesized for the formation of nucleic acid, the initial step of protein synthesis (Newsholme, E. A., and Start, C., Regulation in Metabolism, John Wiley and Sons, London, New York, Sydney, Toronto, 1976). after illness the rate of glucose oxidized via the pentose phosphate shunt is more than doubled (Wannemacher, R. W., Jr., Beall, F. A., Canonico, P. G., et al., Metabolism, 29, 201, 1980). A large amount of glucose derived from amino acids during the process of gluconeogenesis after trauma enters this pathway thus contributing to the loss of protein.
During prolonged periods of illness like renal failure, cancer and respiratory therapy and notwithstanding conventional intravenous feeding, a significant loss of body weight is often observed. Of major concern to all in this field of nutritional support is the loss in body mass, i.e., muscle, organs, etc. This loss correlates to a loss of body nitrogen. When amino acids originating from lean body mass are converted to glucose in the liver, urea is generated and excreted in the urine. The determination of urinary urea-nitrogen content can, therefore, indicate a decrease in lean body mass. By measuring nitrogen intake and output, a nitrogen balance can be made. A nitrogen excretion exceeding the intake is often seen after trauma, sepsis, and other severe illness and can result in morbidity, even mortality. Protein depletion, particularly of visceral organs, represents the single most important unresolved aspect of illness today. A loss of 30% of the original body weight during intravenous feeding in a seriously ill patient very often leads to death (Hadley, H. D., "Percent of Weight Loss: A Basic Indicator of Surgical Risk", Journal American Medical Assoc., 106, 458, 19 and Taylor and Keyes, "Criteria of Physical Fitness in Negative Nitrogen Balance", Ann. N.Y. Acad. Sc., 73, 465, 1958).
Attempts at feeding patients intravenously are complicated because the intravenous route represents an abnormal method of administering nutrients in the body. During oral food intake, the hepatic portal vein drains most of the absorption area of the gut so that apart from long chain triglycerides, which are taken up via the thoracic lymph duct, dietary nutrients are absorbed via the portal vein (Havel, R. J., N. Engl. J. Med., 287, 1186, 1972). Most compounds that are absorbed from the gut pass through the liver, and therefore, the liver is forceably situated to function as the initial regulator of the blood systemic level of many compounds that enter the body through the gut. This regulating function of the liver is especially important regarding glucose uptake and utilization. After an oral carbohydrate containing meal, glucose concentrations in the portal blood increase from about 5 to 40 mM or more while peripheral blood glucose concentrations range only from 4 to maximally 10 mM. The ability of the liver to remove glucose from the portal blood is guaranteed by an enzyme, glucokinase, which is only found in the liver.
Glucokinase activity is regulated by portal venous glucose and insulin levels. In contrast to oral food intakes, during intravenous glucose infusions, portal venous blood glucose concentrations do not reach high peak levels as after oral uptake and glucokinase activity remains relatively low (Jshida, T., Chap., S., Chuo, J., Lewis, R., Hartley, C., et al., J. Clin. Invest., 72, 590, 1983) so that liver is not capable in functioning as a buffer for glucose homeostasis. Therefore, during an intravenous glucose infusion, as is observed during standard parenteral nutrition feedings, the delicate inter-relationship between substrates transported in the blood and their effect upon intermediary metabolism in various organs is determined by unphysiologically high systemic blood glucose and insulin levels. In contrast, the object of the present invention is the use of xylitol and amino acids to provide the patient with an energy source which is converted in the liver to glucose so that during intravenous feeding the liver can again regulate glucose homestasis.
Although the most frequently used carbohydrate for intravenous feeding is glucose, recent studies have demonstrated that hepatic glucose output is substantially diminished by the infusion of 0.06 to 0.12 gm glucose per kilogram per hour (100-200 g/day). Intravenous administration of glucose above the endogenous synthesis rate causes only a marginal further reduction in endogenous glucose production. Under optimal conditions, only 30 percent of glucose entering the liver is directly oxidized; the remainder is converted to glycogen or fat. The percentage of glucose oxidized declines above an infusion rate of 0.12 gm per kilogram per hour (Wolfe, R. R., Allsop, J. R., Burke, J. F., Metabolism, 28, 210, 1979).
During intravenous infusion of 600 gm glucose together with amino acids, approximately 130 gm of triglyceride are synthesized in the liver. These triglycerides are bound to lipoproteins and relesed as VLDL triglycerides. The rate-limiting step during hepatic lipogenesis is not the conversion of glucose to fatty acids and the esterification to triglycerides, but the incorporation of triglycerides into the VLDL fraction. It is easily understood that continuous intravenous glucose infusion at high rates will exceed the capacity of the liver to synthesize VLDL triglycerides. The accumulation of triglycerides results in periportal fatty infiltration and a rise of liver specific enzymes.
Large intravenous doses of glucose also produce hyperglycemia and hyperinsulinemia. An increase in secretion of insulin and to a greater extent, the administration of exogenous insulin reduces muscle catabolism, thereby improving nitrogen balance. Under these circumstances, protein synthesis is shifted to the peripheral organs, mainly to muscle tissue (Woolfson, A. M. J., N. Engl., J. Med., 300, 14, 1979). Intravenous administration of glucose in excess of 0.06 g/kg BW.h (100 g/day) results in a progressive decline of total protein, albumin, pre-albumin, retinol-binding protein, and transferring (Loehlein, D., Zick, R., Infusions therapy, 8, 133, 1981) concentrations.
Because intravenously administered glucose bypasses the liver, the organ of blood glucose homeostasis, even rates of 0.12 gm per kilogram per hour are associated with a significant increase in blood glucose and insulin levels in ill patients. (Elwyn, D. H., Kinney, J. M., Jeevanadam et al., Ann. Surg., 190, 177, 1979). Most important, however, gluconeogenesis and the concomitant loss of lean body mass is not reduced. As the gut mucosa also contributes to protein wasting by increasingly releasing amino acids during illness, any intravenous nutritional therapy not reducing protein wasting, will simultaneously prolong the availability of adequate oral nutrient uptake, which is unquestionably the most efficient route for feeding a patient.
In contrast to the present art, a goal of this invention in feeding the patient with renal failure, respiratory therapy and cancer cachexia is to moderate blood glucose and insulin elevations and to attenuate the loss of lean body mass by reducing gluconeogenesis. Xylitol oxidation is insulin independent without hyperglycemia (DeKalermatten, N., Ravussin, E., Maeder, E., et al., Metabolism, 29, 62, 1980). It enters the pentose phosphate shunt directly and does not require insulin. The maximal turnover capacity is elevated during illness in contrast to glucose. Maximal xylitol disposal rate in man during normal metabolic conditions is 0.37 g/kg BW.h (620 g/day). Depending on the severity of an illness, the maximal disposal rate may increase to 0.6 g/kg BW.h (1000.0 g/day) and 0.76 g/kg BW.h (1277 g/day) (Ackermann, R. H., Infusion Therapie, 7, 113, 1980) respectively. In contrast to xylitol, maximal glucose disposal rates after illness are reduced by approximately 36% from 1440 g/day to 925 g/day, even supraphysiologic insulin concentrations are not capable of increasing the limit during illness (Black, P. R., Brooks, D. C., Bessey, P. Q. et al., Ann. Surg., 196, 420, 1982). Unlike, glucose, intravenously administered xylitol is primarily metabolized in the liver and there converted to glucose independent of insulin. (Pellaton, M., Acheson, K., Maeder, E. et al., JPEN, 2, 627, 1978).
Insulin concentrations higher than basal levels are not needed for utilization of xylitol when infused at low rates of 0.08-0.1 g/kg BW.h (125-185 g/day). At these infusion rates xylitol not only will not stimulate insulin release but also will not require insulin to be metabolized to the triose part of the glycolytic pathway. Insulin, however, is needed for further metabolism. Thus, the generation of glucose-6-phosphate in the liver cells requires far less insulin than that required for the activation of glucose.
Previous studies have shown that during long term infusion of xylitol alone at a rate of 0.125 g/kg BW.h (210 g/day) in healthy volunteers, blood glucose levels actually decrease, due to reduced gluconeogenesis, since during its intravenous infusion, xylitol leads to a higher glycogen deposition than glucose, and glycogen is one of the most potent inhibitors of gluconeogenesis. In addition, the concentration of insulin needed for preventing gluconeogenesis is likely to be much lower than that needed for the activation of glucose in the liver cell.
At present, xylitol has either only been used as part of hypertonic carbohydrate mixture solution consisting of glucose, fructose, xylitol in preparation of 200 g/200 g/200 g with a total intake of 600 g/per day or given to unstressed or only mildly stressed patients. The presently available xylitol and amino acid mixture solution is only to be used as a part of a hypercaloric infusion regimen. This xylitol/amino acid solution also contains electrolytes, is hypertonic, and cannot be given into a peripheral vein. The ability of peripherally administerably xylitol and amino acid solution to preserve protein in a patient suffering from renal failure, cancer cachexia or undergoing respiratory therapy and in fact would be unexpected from the prior art. The use of hypertonic xylitol together with amino acids in elective surgery patients in contrast results in significantly higher nitrogen excretion in the urine and is thus not protein sparing and in fact caused larger amounts of protein wasting because of the large amino acid amounts administered (Georgieff, M., Kattermann, R., Geiger, K., et al., Infusions Therapie, 2, 69, 1981). Therefore, the art concerning xylitol and amino acid preparations suggests that such infusions would not be useful in critically ill patients.
It is the object of the present invention to provide an energy source which can be used together with amino acids for a patient obliged to receive nutritional requirements via parenteral administration to optimize the nutritional regimen. In this regard, it is an object to provide an energy source which is compatible for prolonged use in the substrate homeostasis which results in nitrogen-sparing of a patient who is suffering from renal failure, cancer cachexia and respiratory therapy and which will promote host defense, immune competence, non-sepis, fast resumption of oral nutrient intake, and survival of the patient.* This goal is obtained through this invention, in which a novel preparation and a method of administering it is disclosed to support the above mentioned ill patient and reduce protein-wasting and gluconeogenesis by using isotonic hypocaloric preparations of xylitol and amino acids which together reduce protein wasting and supporting hepatic protein synthesis and function. This combination results in an unexpected improvement of nitrogen balance in contrast to giving xylitol or the amino acids alone. FNT *My invention uses specifically less of both xylitol and amino acids and surprisingly results in a product which cannot only administered in a peripherial vein but more importantly in a product which spares protein (i.e., Nitrogen sparing).